Nutrition Research and Practice (Nutr Res Pract) 2010;4(6):492-498
DOI: 10.4162/nrp.2010.4.6.492
Low HDL cholesterol is associated with increased atherogenic lipoproteins and insulin
resistance in women classified with metabolic syndrome
1§
1
1
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1
Maria Luz Fernandez , Jennifer J Jones , Daniela Ackerman , Jacqueline Barona , Mariana Calle ,
Michael V Comperatore1, Jung-Eun Kim1, Catherine Andersen1, Jose O Leite1, Jeff S Volek1, Mark McIntosh2,
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3
4
Colleen Kalynych , Wadie Najm and Robert H Lerman
1
Department of Nutritional Sciences, University of Connecticut, 3624 Horsebarn Road Ext, Storrs, CT 06269, USA
Department of Emergency Medicine, University of Florida, Jacksonville FL, USA
3
Department of Family Medicine, University of California, Irvine, CA, USA
4
MetaProteomics LLC, Gig Harbor, WA, USA
2
Abstract
Both metabolic syndrome (MetS) and elevated LDL cholesterol (LDL-C) increase the risk for cardiovascular disease (CVD). We hypothesized
that low HDL cholesterol (HDL-C) would further increase CVD risk in women having both conditions. To assess this, we recruited 89 women
with MetS (25-72 y) and LDL-C ≥ 2.6 mmol/L. To determine whether plasma HDL-C concentrations were associated with dietary components,
circulating atherogenic particles, and other risk factors for CVD, we divided the subjects into two groups: high HDL-C (H-HDL) (≥ 1.3 mmol/L,
n = 32) and low HDL-C (L-HDL) (< 1.3 mmol/L, n = 57). Plasma lipids, insulin, adiponectin, apolipoproteins, oxidized LDL, Lipoprotein(a), and
lipoprotein size and subfractions were measured, and 3-d dietary records were used to assess macronutrient intake. Women with L-HDL had higher
sugar intake and glycemic load (P < 0.05), higher plasma insulin (P < 0.01), lower adiponectin (P < 0.05), and higher numbers of atherogenic lipoproteins
such as large VLDL (P < 0.01) and small LDL (P < 0.001) than the H-HDL group. Women with L-HDL also had larger VLDL and both smaller
LDL and HDL particle diameters (P < 0.001). HDL-C was positively correlated with LDL size (r = 0.691, P < 0.0001) and HDL size (r = 0.606,
P < 0.001), and inversely correlated with VLDL size (r = -0.327, P < 0.01). We concluded that L-HDL could be used as a marker for increased
numbers of circulating atherogenic lipoproteins as well as increased insulin resistance in women who are already at risk for CVD.
Key Words: Metabolic syndrome, heart disease risk, low HDL cholesterol, atherogenic lipoproteins, insulin resistance
Introduction7)
The metabolic syndrome (MetS) is a constellation of metabolic
abnormalities characterized by abdominal obesity, hyperglycemia,
high blood pressure, and dyslipidemias including elevated
apolipoprotein B (apo-B), high plasma triglycerides (TG), increased
numbers of small, dense LDL particles, and low HDL-cholesterol
(HDL-C) concentrations [1]. The cluster of these characteristics
poses individuals at higher risk for both cardiovascular disease
(CVD) and type 2 diabetes [2].
The inverse association between low plasma concentrations of
HDL-C and atherosclerosis has been clearly established [3]. The
protective effects of HDL against CVD risk are not limited to
the role of this lipoprotein in reverse cholesterol transport [4].
HDL has a number of pleiotropic functions, including the
transport of paraoxonase 1, an important anti-oxidant in plasma
[5], as well as the promotion of cholesterol removal from
macrophages [6], regulation of endothelial adhesion molecule
expression [7], anti-inflammatory effects [8], and nitric oxide
promoting action [9]. What is clear from previous studies [4-9]
is that elevated concentrations of HDL-C are protective against
CVD and atherosclerosis through many different mechanisms.
This protective role of HDL may also be extended to subjects
who present other risk factors for heart disease.
Dietary carbohydrate has been shown to modulate the risk
factors associated with MetS [10]. For example, carbohydraterestricted diets decrease plasma TG [11], elevate HDL-C [12],
and reduce the number of circulating small LDL [13]. Since fat
accumulation in the trunk area has been shown to be associated
with increased free fatty acid release, insulin resistance, and
disruption of glucose metabolism [10], reductions of fat in this
area are quite beneficial to reduce the risk of CVD and type
2 diabetes [2]. The primary aim of the present study was to
investigate whether low concentrations of HDL-C would result
in increased numbers of atherogenic lipoproteins and insulin
resistance in women already at risk for CVD. Based on this,
§
Corresponding Author: Maria Luz Fernandez, Tel. 1-860-486-5547, Fax. 1-860-486-3674, Email. [email protected]
Received: July 9, 2010, Revised: September 16, 2010, Accepted: October 18, 2010
ⓒ2010 The Korean Nutrition Society and the Korean Society of Community Nutrition
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/)
which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Maria Luz Fernandez et al.
we evaluated several risk parameters for CVD and atherosclerosis
in women having high (H-HDL) (> 1.3 mmol/L) versus low
(L-HDL) (< 1.3 mmol/L) plasma HDL-C concentrations. These
subjects had high LDL-C (> 2.6 mmol/L) and were also classified
as having MetS, two conditions that increase CVD risk. A
secondary objective was to determine whether dietary components
were related to low concentrations of HDL-C.
Subjects and Methods
Study design
The subjects for this study were recruited from 3 different
locations: the University of Connecticut (Storrs, CT) (n = 29),
University of Florida (Jacksonville, FL) (n = 47), and University
of California (Irvine, CA) (n = 13). The inclusion criteria were
women with MetS, having at least 2 of the following
characteristics: blood pressure ≥ 130/85 mm Hg or treated
hypertension, waist circumference (WC) > 88 cm, fasting glucose
≥ 5.6 mmol/L, and HDL-C < 1.3 mmol/L, in addition to high
TG (≥ 1.7 mmol/L) and LDL-C ≥ 2.6 mmol/L.
The subjects were recruited by word of mouth, distribution
e-mails, newspaper and radio advertisements, and flyers. The
exclusion criteria were low LDL-C (< 2.6 mmol/L), TG < 1.7
mmol/L, age less than 25 or older than 75 y, pregnancy, lactation,
thyroid problems, stroke, heart disease, or use of medication or
supplements relevant to diabetes or CVD such as hypoglycemic
or cholesterol lowering agents. A total of 89 women were
recruited for the study. All protocols were approved by the
Institutional Review Boards of the respective universities.
Anthropometrics and blood pressure
After obtaining a consent agreement from each participant,
weight and height were measured and body mass index (BMI)
was calculated (kg/m2). WC was calculated by measuring at the
superior border of the iliac crest using a flexible tape. Blood
pressure (systolic and phase-V diastolic) was measured on the
left arm with the subjects seated, after at least 5 minutes rest,
using an automated blood pressure monitor (Omron, Healthcare
Inc., Bannockburn, IL). Three separate recordings were made and
the mean was used.
Diet analysis
The subjects completed a 3-d diet record including one
week-end day to assess energy, carbohydrate, fat, protein, dietary
fiber, and cholesterol intake as well as glycemic load, which was
automatically calculated. The dietary records were analyzed using
The Nutrition Data System 9.0 (Minneapolis, MN).
493
Laboratory measurements
After a 12-h overnight fast, 60 ml of fasting blood was
collected from all participants. Plasma was separated from red
blood cells by centrifugation at 2000 × g, aliquoted, and then
frozen at -80℃ for further analysis. Plasma lipids, glucose,
insulin, apo B, and apo A-I were measured in a certified
laboratory (Northwest Lipid Research Laboratories, Seattle, WA).
Plasma glucose and lipids were assayed using a Vitros 950IRC
analyzer (Ortho-Clinical Diagnostics, Rochester, NY). LDL-C
was determined indirectly using the Friedewald equation [14].
Apo A-I and B were analyzed by turbidimetry using an Advia
1650® (Bayer Diagnostics, Tarrytown, NY). Insulin was
determined by a chemiluminescent, immunometric assay using
a DPC Immulite 2000 (Diagnostics Products Corporation, Nutley,
NJ). The homeostasis model assessment (HOMA) [15] was
calculated as a measure of insulin resistance.
Lipoprotein subfractions and size
H-NMR analysis was performed (LipoScience, Inc., Raleigh,
NC) using a 400 MHz NMR analyzer (Bruker BioSpin Corp,
Billerica, MA) as previously described [13]. NMR simultaneously
quantifies > 30 lipoprotein subclasses that are empirically
grouped into 9 smaller subclasses based on the following particle
diameters: large VLDL (35-60 nm), medium VLDL (27-35 nm),
small VLDL (23-27 nm), large LDL (21.2-23 nm), medium LDL
(19.8-21.2 nm), small LDL (18-19.8 nm), large HDL (8.8-13 nm),
medium HDL (8.2-8.8 nm), and small HDL (7.3-8.2 nm).
Weighted-average lipoprotein particle sizes in diameter were
calculated based on the diameter of each lipoprotein subclass
multiplied by its respective relative concentration.
Apolipoproteins A-II, C-II, C-III, and E
Apolipoproteins were measured using LINCOplex: Multiplex
Biomarker Immunoassay for Luminex Instrumentation/xMAP
Technology (Austin, TX). This technique uses fluorescently
labeled microsphere beads with antibodies specific to each
individual apolipoprotein [16]. The technique is well standardized
in our laboratory [11].
LDL oxidation and Lipoprotein(a)
LDL oxidation was measured by ELISA kits (ALPCO, Salem,
NH) using the monoclonal antibody 4E6, which has been utilized
in numerous clinical trials [17]. The standards and samples were
read at 450 nm in a spectrophotometer (Spectramax Multimode
Spectrophotometer, Sunnyvale, CA). Using a polynomial curve,
concentrations of oxidized LDL were calculated and expressed
as mmol/L. Plasma Lp(a) was determined in duplicate using a
sandwich ELISA (Diagnostic Automation, Inc., Calabasas, CA)
with a dynamic range of 0.04-5.89 µmol/L. Absorbance was
494
Low HDL in the metabolic syndrome
determined using the same spectrophotometer as previously
reported [18].
Table 1. Anthropometrics, blood pressure, plasma lipids, glucose, insulin and
apolipoproteins (apo) of women classified with MetS having low (< 1.3 mmol/L)
or high (≥ 1.3 mmol/L) HDL-C1)
High HDL-C (n = 32)
Low HDL-C (n = 57)
Adiponectin and intercellular adhesion molecule-1 (sICAM-1)
Age (yr)
47.6 ± 9.8
46.6 ± 10.7
Weight (kg)
93.0 ± 17.0
90.3 ± 13.1
BMI (kg/m2)
34.2 ± 5.7
34.0 ± 5.0
WC (cm)
110.7 ± 11.9
107.6 ± 10.5
Systolic (mm Hg)
127.8 ± 13.3
126.8 ± 15.9
Diastolic (mm Hg)
81.0 ± 7.7
78.8 ± 8.9
TC (mmol/L)
5.96 ± 0.80
5.66 ± 0.85
Parameter
From fasting plasma, ICAM-1 and adiponectin were measured
in duplicate in the same assay using Human CVD Panel 1
LINCOplex kits. Samples were diluted 1:100 and simultaneously
quantified by using Antibody-Immobilized Beads and Luminex
xMAP technology. All assays were carried out on the same day
to decrease variability. The coefficient variation was 2-6%. The
sensitivities for sICAM-1 and adiponectin were 9.0 pg/ml and
56.0 pg/ml, respectively, as previously reported [19].
Statistical analysis
Data are presented as mean ± SD for the measured parameters.
Since we had different numbers of subjects in the low and high
HDL-C groups, the non-parametric Mann-Whitney U test was
performed to assess differences in plasma lipids, apolipoproteins,
diet, inflammatory markers, and lipoprotein size and subfractions.
P < 0.05 was considered significant. Pearson correlations were
conducted between HDL-C and the different lipoprotein sizes.
LDL-C (mmol/L)
3.50 ± 0.85
3.56 ± 0.72
HDL-C (mmol/L)
1.48 ± 0.16
1.03 ± 0.16**
TG (mmol/L)
2.17 ± 0.38
2.37 ± 0.67
Glucose (mmol/l)
4.86 ± 0.70
4.97 ± 0.80
Insulin (µU/mL)
13.2 ± 6.2
18.8 ± 9.9*
Insulin resistance (HOMA)
3.2 ± 1.6
4.5 ± 2.8*
Adiponectin (mg/L)
16.4 ± 6.8
13.8 ± 7.4*
ICAM (mg/L)
0.094 ± 0.027
0.17 ± 0.049*
Apo B (mg/L)
1,115.3 ± 210.8
1,216.0 ± 217.4
Apo A-I (mg/L)
1711 ± 250
1415 ± 161**
Apo A-II (mg/L)
225.5 ± 83.8
168.5 ± 51.7**
Apo C-II (mg/L)
100.9 ± 34.1
87.0 ± 38.7*
Apo C-III (mg/L)
284.6 ± 99.3
252.9 ± 119.5*
Apo E (mg/L)
75.9 ± 37.2
71.5 ± 28.3
1)
Results
All 89 women recruited for the study were classified as having
MetS. All women (100%) had high TG (≥ 1.7 mmol/L), as this
was one of the inclusion criteria, and 99% had WC > 88 cm.
Fasting blood glucose > 5.6 mmol/L, high blood pressure (≥
130/85 mm Hg), and low HDL-C (< 1.3 mmol/L) accounted for
39, 47, and 64% of the subjects, respectively (Fig. 1).
We divided the women into two groups according to the
following concentrations of plasma HDL-C: H-HDL ≥ 1.3
mmol/L and L-HDL < 1.3 mmol/L, to evaluate whether lower
HDL-C would be associated with higher risk for atherosclerosis.
Values are mean ± SD for the number of subjects indicated in parentheses.
* Significantly different at P < 0.05, ** Significantly different at P < 0.001 as determined
by Mann-Whitney U non-parametric test
Table 2. Total Energy, fat, carbohydrate, protein, dietary cholesterol and dietary
fiber intake obtained from a 3-d dietary record of women classified with MetS
having low (< 1.3 mmol/L) or high (≥ 1.3 mmol/L) HDL-C1)
High HDL-C (n = 32)
Low HDL-C (n = 57)
Total energy (Kjoules/d)
Parameter
8,622 ± 3,349
8,921 ± 3,374
Total fat (g/d)
101.8 ± 55.0
92.6 ± 46.9
Total fat (% energy)
38.5 ± 7.4
36.5 ± 7.7
Saturated fat (% energy)
13.5 ± 3.5
12.0 ± 3.2*
Monounsaturated fat
(% energy)
14.8 ± 4.5
13.6 ± 3.1
Polyunsaturated fat
(% energy)
9.5 ± 8.3
7.9 ± 3.2
Trans fatty acids (g/d)
4.4 ± 2.9
5.4 ± 3.5
Omega-3 fatty acids (g/d)
1.9 ± 1.2
1.9 ± 1.1
Total carbohydrate (g/d)
211.5 ± 101.3
234.2 ± 86.4
Carbohydrate (% energy)
42.2 ± 8.1
44.7 ± 10.0
Total sugars(g/d)
76.4 ± 48.9
103.1 ± 58.9*
Added sugars (g/d)
48.5 ± 42.0
76.4 ± 56.2*
Glycemic Load
116.4 ± 60.4
133.3 ± 53.2*
Total protein (g/d)
79.7 ± 41.7
86.1 ± 29.6
Protein (% energy)
15.9 ± 4.0
17.0 ± 4.4
321.2 ± 168.9
331.0 ± 173.
Dietary cholesterol (mg/d)
Alcohol (% energy)
Total fiber (g/d)
Fig. 1. Percent of subjects with waist circumference (WC) > 88 cm, blood
pressure > 130/85 mm Hg; plasma glucose > 100 mg/dL (5.6 mmol/L); plasma
triglycerides (TG) > 150 mg/dL (1.7 mmol/L) and HDL < 50 mg/dL (1.3 mmol/L)
in women classified with metabolic syndrome (MetS) (n = 89)
3.2 ± 5.2
2.4 ± 5.8*
18.3 ± 10.8
16.4 ± 8.1
Soluble fiber (g/d)
5.6 ± 3.1
5.3 ± 2.5
Insoluble fiber (g/d)
12.5 ± 8.3
10.9 ± 6.4
1)
Values are mean ± SD.
* Indicates significantly different (P < 0.05) as determined by Mann-Whitney nonparametric test
Maria Luz Fernandez et al.
A
495
Table 3. Number of VLDL, IDL, LDL and HDL particles according to size,
apolipoproteins, VLDL, LDL and HDL diameters, LDL oxidation and Lp(a) of
women classified with MetS having low (< 1.3 mmol/L) or high (≥ 1.3 mmol/L)
HDL-C1)
Parameter
B
High HDL-C (n = 32)
Low HDL-C (n = 57)
VLDL diameter (nm)
51.1 ± 7.0
54.7 ± 8.1*
Total VLDL (mmol/L)
97 ± 33
104 ± 39
Large VLDL (mmol/L)
4.8 ± 3.1
8.4 ± 7.8*
Medium VLDL (mmol/L)
35.9 ± 17.5
41.6 ± 24.6
Small VLDL (mmol/L)
56.5 ± 18.6
53.6 ± 20.7
IDL (mmol/L)
65.4 ± 53.1
87.1 ± 49.7*
LDL diameter (nm)
21.0 ± 0.6
20.2 ± 0.6*
Total LDL (mmol/L)
1490 ± 366
1734 ± 345*
Large LDL (mmol/L)
513 ± 158
288 ± 169*
Small LDL (mmol/L)
932 ± 388
1,359 ± 384*
HDL diameter (nm)
8.9 ± 0.3
8.6 ± 0.2*
Total HDL (mmol/L)
39.5 ± 6.2
33.6 ± 4.9*
Large HDL (mmol/L)
8.3 ± 3.5
4.2 ± 2.4*
Medium HDL (mmol/L)
6.9 ± 5.6
6.3 ± 4.6
Small HDL (mmol/L)
24.3 ± 6.9
23.1 ± 5.3
Oxidized LDL (µg/L)
112.1 ± 94.8
118.6 ± 98.7
Lp(a) (µmol/L)
0.92 ± 0.81
0.69 ± 0.72
1)
C
Fig. 2. Correlations between HDL-C and VLDL size (panel A) HDL size (panel
B) and LDL size (panel C)
As indicated in Table 1, age, BMI, WC, weight, and systolic
and diastolic blood pressure were not different between groups.
Likewise, the risk factors of total cholesterol, LDL-C, apo B,
apo E, and glucose were not different between the high and low
HDL groups. However, HDL-C (by definition), apo A-I, apo
A-II, apo C-II, and apo C-III were higher in the H-HDL group.
Insulin, HOMA, adiponectin, and ICAM were lower (P < 0.0001)
in the H-HDL group (Table 1).
Regarding dietary intake, women from the H-HDL group
consumed more saturated fat, as well as energy from alcohol
(P < 0.05), while they consumed less sugar and added sugar than
subjects in the L-HDL group (Table 2). Other dietary components
including total fat, protein, dietary cholesterol, fiber, and different
types of fatty acids were not different between groups. Positive
correlations were found between HDL-C and LDL size (r =
0.628, P < 0.0001) and HDL size (r = 0.606, P < 0.0001), and
Values are mean ± SD. Values in a row with different superscripts are significantly
different (P < 0.01) as determined by Mann-Whitney non-parametric test
a negative correlation was found between HDL-C and VLDL
size (r = -0.327, P < 0.01) (Fig. 2).
Concentrations of lipoprotein subclasses, lipoprotein size,
oxidized LDL, and Lp(a), which are major biomarkers of
atherosclerosis risk, were also evaluated in women with high or
low concentrations of HDL-C (Table 3). The H-HDL group
presented a less atherogenic lipoprotein profile with lower
concentrations of large VLDL, small LDL, and IDL compared
to the L-HDL group. Furthermore, lipoprotein size was modified
by the concentration of HDL-C in plasma. Women with L-HDL
had lower numbers of large LDL (P < 0.0001), and therefore a
smaller LDL diameter (P < 0.01) than those from the H-HDL
group. The L-HDL group also had larger VLDL (P < 0.05) and
smaller HDL (P < 0.05) diameters than the H-HDL group (Table
3). Concentrations of oxidized LDL and Lp(a) had a wide range
among participants; however, they were not different between
HDL groups (Table 3).
Discussion
In this study we evaluated the adverse effects of HDL-C in
concentrations of less than 1.3 mmol/L in women with high risk
for CVD, mainly a population classified with MetS and the
additional risk factor of plasma LDL-C ≥ 2.6 mmol/L. Our data
analysis suggests that HDL-C < 1.3 mmol/L further increases the
risk of CVD and atherosclerosis. The novel aspect of this study
is that L-HDL appears to be a biomarker of elevated
concentrations of circulating atherogenic lipoproteins as well as
increased insulin resistance and lower concentrations of
496
Low HDL in the metabolic syndrome
adiponectin, all of which are key biomarkers of increased risk
for type 2 diabetes and coronary heart disease. Although
participants in this study had dietary habits that might increase
risk for heart disease such as a high intake of trans fatty acids
and low intakes of omega-3 fatty acids and dietary fiber, high
simple sugar intake and high glycemic load were the dietary
components that might have been correlated with low
concentrations of HDL-C.
A main concern regarding MetS is the predisposition to glucose
intolerance, insulin resistance, and diabetes [2]. The consumption
of foods with a low glycemic index has been advocated for
amelioration of dysfunctional glucose metabolism for more than
two decades [20]. Diets based on varying degrees of carbohydrate
restriction also have demonstrated efficacy in improving glucose
metabolism and associated metabolic aberrations [10]. In the
present, study, the women with lower HDL-C (< 1.3 mmol/L)
consumed more sugar and had higher glycemic loads than those
from the H-HDL group. Interestingly, women from the L-HDL
groups also consumed less alcohol and less saturated fat.
Moderate increases in alcohol have been correlated with higher
HDL-C and paraoxanase-1, suggesting a protective effect against
CVD [21], and all fatty acids including saturated fatty acids (with
the exception of trans fat) have been correlated with increased
HDL-C [22]. Thus, the above results are not surprising.
The women with L-HDL also had higher concentrations of
plasma insulin and greater insulin resistance as determined by
HOMA, along with lower concentrations of adiponectin. In
agreement with our results, low adiponectin concentrations are
strongly correlated with insulin resistance [23]. Data from
epidemiological studies also indicate that circulating adiponectin
is reduced in patients with CVD and diabetes [24]. To further
support our findings that HDL-C concentrations predict insulin
resistance, in a recent study, TG/HDL-C was used as a marker
of insulin resistance in obese patients [25]. In the present study,
plasma TG levels did not differ between groups and subjects
from the H-HDL group had higher apo C-III than those from
the L-HDL group. These findings suggest that the higher levels
of apo C-III in the H-HDL group were related to the increased
number of HDL particles available to transport this
apolipoprotein. While apo C-III present in VLDL is associated
with decreased lipoprotein lipase activity, apo C-III transported
by HDL indicates a reservoir of this apolipoprotein [26]. Overall,
subjects from the L-HDL group appear to be at greater risk for
the development of diabetes as documented by more elevated
insulin resistance and lower levels of adiponectin.
Subjects with L-HDL presented increased concentrations of the
atherogenic lipoproteins large VLDL, small LDL, and IDL.
Furthermore, these women had lower concentrations of the larger,
more buoyant LDL that is considered less atherogenic [27]. In
addition, impaired endothelial function can be assessed by
measuring the level of molecules secreted by the endothelium,
such as sICAM1 [28]. Subjects with L-HDL had increased
concentrations of this adhesive molecule, which poses at higher
risk for CVD.
Abnormalities in VLDL particle size seem to be a major
contributing factor to dysfunctional lipoprotein metabolism [29].
Large VLDL particles are classified as atherogenic for two main
reasons: their ability to interact with macrophages in the arterial
wall [30] and their easy conversion to small LDL [31]. In addition
to transporting high concentrations of plasma TG, large VLDL
also carry high concentrations of cholesterol (5 times more than
an LDL particle) [30]. These large VLDL are taken up by
macrophages through cell surface membrane-binding proteins
leading to the formation of foam cells and the initiation of
atherosclerosis. In addition, through the delipidation cascade,
TG-rich VLDL are precursors for the formation of small, dense
LDL particles and increased HDL catabolism [32]. The
phenotype characterized by a predominance of small LDL
particles has been termed pattern B and is typical of MetS and
diabetes [27]. Small, dense LDL particles are considered more
atherogenic due to their decreased binding to the LDL receptor,
leading to increased plasma residence time and an increased
susceptibility to oxidation [33]. In addition, increased levels of
small LDL in plasma are associated with increased risk of
coronary heart disease [33]. IDL, also known as VLDL remnants,
are part of TG-rich lipoproteins and are associated with increased
risk for heart disease [34]. All of these atherogenic lipoproteins
were higher in women with lower concentrations of HDL-C.
Another observation was that the groups of women with HDL-C
> 1.3 mmol/L had lower numbers of both total HDL and large
HDL particles. Since the main function of HDL is to remove
cholesterol and oxysterols from extra-hepatic cells including
smooth muscle cells, endothelial cells, and macrophages through
ABCA1 and ABCG1 transporters [35], a higher number of
particles suggest a more efficient reverse cholesterol transport
and increased protection against atherosclerosis.
Both Lp(a) levels and oxidized LDL concentrations did not
differ between HDL groups. Plasma Lp(a) concentrations are
reported to have a strong ethnic influence and is correlated with
increased risk for heart disease both through its atherogenic and
prothrombotic properties [36]. Specifically, concentrations >
0.71-1.07 µmol/L are associated with 1.5- to 3-fold increases
of coronary atherosclerosis independent of plasma levels of other
lipoproteins [36]. In the current study with women at high risk
for CVD, levels of Lp(a) varied between 0.21 and 4.14 µmol/L.
Low HDL-C was not associated with higher concentrations of
Lp(a) in this group of women. Oxidized LDL has been correlated
with atherosclerosis, diabetes, and renal disease [37]. Small
significant amounts of oxidized LDL have been detected in
plasma by use of monoclonal antibodies specific to epitopes of
oxidized apo B [17]. Among these, 4E6 recognizes MDA
modified lysine epitopes and has been extensively used in human
studies [17]. Similar to our findings for Lp(a), the women in
the current study presented a wide range of oxidized LDL, from
1.4 to 445 μgl/L. In this group of women, concentrations of both
biomarkers, Lp(a) and oxidized LDL, for increased risk of CVD,
Maria Luz Fernandez et al.
were independent of HDL-C concentrations.
The data from this study suggest that low plasma HDL-C (<
1.3 mmol/L) is associated with increased risk of CVD and
diabetes in women already at risk, and appears to be a biomarker
of a greater atherogenic lipoprotein profile (decreased large
VLDL and small LDL). In addition, low concentrations of
HDL-C are related to a lower number of HDL particles, decreased
HDL size, and decreased large HDL, conditions that suggest the
existence of a less efficient reverse cholesterol transport. Finally,
individuals with low concentrations of HDL-C were at increased
risk for diabetes, as they presented increased insulin resistance
and lower concentrations of adiponectin.
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